ErbB3 receptor tyrosine kinase (RTK) and its associated signaling regulate the development, maturation and function of the peripheral nervous system (PNS). Here we describe a new alternatively spliced ErbB3 variant (nuc-ErbB3) that is localized in the nucleus of Schwann cells (the glial cells of the PNS). Based on our preliminary data, nuc-ErbB3 controls proper axon recognition, axonal sorting and myelination by Schwann cells independent of the full-length ErbB3 receptor. nuc- ErbB3 possesses a functional nuclear localization signal sequence and binds to transcriptionally active chromatin. Using ChIP-ChIP arrays we identified the gene promoters that interact with nuc- ErbB3 and clustered the active promoters in Schwann cell gene expression. Our long-term objective is to elucidate the function of nuc-ErbB3 as a transcription factor and understand its role during the establishment of Schwann cell neuron interactions and myelination. Specifically, we aim to: 1. Determine the functional significance of nuc-ErbB3 in the establishment of axon-glial interactions and myelination, 2. Reveal the role of nuc-ErbB3 as a transcriptional regulator that influences the interaction of Schwann cells with axons and 3. Identify protein-binding partners of nuc-ErbB3 in the nucleus of Schwann cells and determine how they modulate nuc-ErbB3 function. We believe that the accomplishment of these aims will reveal a new concept for membrane receptor tyrosine kinase regulation of cellular processes in the nervous system through their alternatively spliced nuclear variants. Moreover, exploration of the transcriptional role of nuc-ErbB3 and its function during axon-glial interactions and myelination will provide useful information in relation to peripheral neuropathies caused by deregulated gene expression and/or altered myelin formation. PUBLIC HEALTH RELEVANCE: The molecular events underlying the initial interaction of glial cells with axons in the vertebrate nervous system are poorly understood. However, these events determine the proper development of the nervous system and the extent of myelination and functional recovery following injury. In the peripheral nervous system (PNS), the predominant regulator of proliferation, myelination and re- myelination by Schwann cells is neuregulin/ErbB2-3 receptor signaling. In our proposal we describe a nuclear variant of ErbB3 receptor tyrosine kinase (nuc-ErbB3) that is produced by alternative splicing. We believe the role of nuc-ErbB3 is very important for the establishment of proper axon-glial interactions and myelination in the PNS and subsequently we propose experiments to study the role of nuc-ErbB3 as a transcriptional regulator of Schwann cell responses.